An efficient procedure for the preparation of carboxamides and peptides using in situ generated N-succinimidyl active esters

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An Efficient Procedure for the
Preparation of Carboxamides and
Peptides using in situ Generated N-
Succinimidyl Active Esters
Ki-Jong Hana & Misoo Kimb
a Department of Molecular Science and Technology, Ajou University,
206 World cup-Ro, Suwon, Kyonggi-Do, Republic of Korea
b Department of Basic Science, Hankyong National University, 327
Jungang-Ro, Ansung, Kyonggi-Do, Republic of Korea
Published online: 10 Jul 2014.
To cite this article: Ki-Jong Han & Misoo Kim (2014) An Efficient Procedure for the Preparation
of Carboxamides and Peptides using in situ Generated N-Succinimidyl Active Esters, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 46:4, 370-375,
DOI: 10.1080/00304948.2014.922380
To link to this article: http://dx.doi.org/10.1080/00304948.2014.922380
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Organic Preparations and Procedures International, 46:370–375, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.922380
OPPI BRIEF
An Efficient Procedure for the Preparation of
Carboxamides and Peptides using in situ Generated
N-Succinimidyl Active Esters
Ki-Jong Han1 and Misoo Kim2
1Department of Molecular Science and Technology, Ajou University, 206 World
cup-Ro, Suwon, Kyonggi-Do, Republic of Korea
2Department of Basic Science, Hankyong National University, 327 Jungang-Ro,
Ansung, Kyonggi-Do, Republic of Korea
The carboxamide moiety is one of the most important functional groups in biologically
active compounds such as peptides.1,2 Most of the preparative methods for carboxamides
and peptides are based on the reaction of an activated carboxylic acid with an amine.3,4
N-Succinimidyl active esters are valuable intermediates in peptide synthesis, since their
reaction with a variety of amines could lead to the corresponding amides.5–7 Triphosgene is
commercially available as a white solid and its utility has been extensively investigated over
the last two decades.8–15 Previously, we reported the synthesis of N-hydroxysuccinimide
esters of carboxylic acids using triphosgene.16 In continuation of our work to develop new
methods using triphosgene as an acid activator,17,18 we report herein an efficient one-pot
procedure for the synthesis of carboxamides and peptides using N-succinimidyl active esters
generated in situ directly from the reaction of carboxylic acids with N-hydroxysuccinimde
(NHS) in the presence of triphosgene (Scheme 1).8
O
O
O
O
R'NH2
(Cl3CO)2CO, NHS
N
R
O
r.t., 1 h
R
N R'
H
Et3N, CH2Cl2
0oC, 30 min
R
OH
O
Scheme 1
In our initial experiments, benzoic acid was smoothly converted to N-succinimidyl
active ester using triphosgene and N-hydroxysuccinimide in the presence of triethylamine.
Received December 6, 2013.
Address correspondence to Misoo Kim, Department of Basic Science, Hankyong National
University, 327 Jungang-Ro, Ansung, Kyonggi-Do, Republic of Korea. E-mail: mkim@hknu.ac.kr
370

Preparation of Carboxamides and Peptieds using N-Succinimidyl Esters
371
Table 1
Synthesis of Carboxamides and Peptides from Carboxylic Acids
Carboxylic
Yield
(%)a
Entry
acid
Amine
Product
1
96
2
3
4
92
91
90
5
6
90
91
7
92
8
9
10
Cbz-L-Phe
Cbz-L-Ile
Cbz-L-Ile
L-Ala-OEt
L-Ala-OEt
L-Leu-OMe
Cbz-L-Phe-L-Ala-OEt
Cbz-L-Ile-L-Ala-OEt
Cbz-L-Ile-L-Leu-OMe
90
92
92
(a) Yields refer to isolated products.
The N-succinimidyl active ester prepared in situ reacted with 4-methylbenzylamine to
give the corresponding carboxamide in 96% yield (Entry 1). To explore the generality and
scope of the one-pot method, various carboxylic acids were examined and the results are
summarized in Table 1. Benzoic acids with electron-donating and electron-withdrawing
groups were efficiently converted to the corresponding carboxamides (Entries 2 and 3).
Cyclohexanecarboxylic acid (Entry 4) and dodecanoic acid (Entry 5) gave the desired
products in high yields. It was found that this method is applicable to Cbz-protected amino

372
Han and Kim
acids such as Cbz-L-alanine and Cbz-L-phenylalanine (Entries 6 and 7). The reaction of
Cbz-L-Phe with L-Ala-OEt afforded the dipeptide, Cbz-L-Phe-L-Ala-OEt in 90% yield
(Entry 8). The reactions with Cbz-L-Ile produced the corresponding dipeptides in high
yields (Entries 9 and 10). Racemization of the dipeptides was observed by comparison of
their reported optical rotation values (Entries 8 and 9).
At first, carboxylic acids are converted into carboxylic acid anhydrides by the triphos-
gene in the presence of triethylamine.19 N-Succinimidyl active esters are then generated in
situ through the reaction of the carboxylic acid anhydrides with N-hydroxysuccinimide.16
The N-succinimidyl esters subsequently react with amines to afford the carboxamides
and peptides. All known products in the Table 1 were characterized by spectral analysis
(IR, 1H NMR and 13C NMR). The spectroscopic data obtained were in agreement with the
structures of the products.
In conclusion, we have developed a simple and efficient one-pot procedure for the con-
version of carboxylic acids into the corresponding carboxamides and peptides using in situ
generated N-succinimidyl active esters. This procedure offers several advantages including
generality and simplicity, easy work-up, clean reactions, and high yields. Applications of
this procedure to the solid-phase peptide synthesis are currently under investigation in our
laboratory and will be reported in due course.
Experimental Section
Triphosgene was purchased from Aldrich Company. Analytical thin layer chromatogra-
phy was performed on pre-coated Merck silica gel 60 F254 TLC plate. Purification was
performed by flash column chromatography by using Merck 230–400 mesh silica gel.
Melting points were determined in capillary tubes on a Bibby Sterilin apparatus and are
corrected. The optical rotations were measured using a Jasco P-1010 digital polarimeter.
Infrared spectra were recorded using a Jasco FT/IR-410 spectrometer with internal calibra-
1
tion. H NMR and 13C NMR spectral data were obtained on a Jeol JNM-ECP 400 MHz
NMR spectrometer. Although triphosgene is a stable commercially available white solid,
one equivalent of triphosgene can produce three equivalents of phosgene.8 Therefore, it is
critical to take extra precautions by working in a hood with strong ventilation.
General Procedure for the Synthesis of Carboxamides and Peptides
To a stirred solution of the carboxylic acid (2.0 mmol, 1.0 eq) in CH2Cl2 (10.0 ml) at 0◦C
were added triphosgene (296.8 mg, 1.0 mmol, 1.5 eq), triethylamine (1.40 ml, 10.0 mmol,
5.0 eq) and N-hydroxysuccinimide (230.2 mg, 2.0 mmol, 1.0 eq). After 30 min, amine
(2.0 mmol, 1.0 eq) was added at 0◦C to the reaction mixture. The reaction mixture was
stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC.
Removal of the solvent by rotary evaporation followed by short path silica gel column
chromatography purification using 50% ethyl acetate in hexane as the mobile phase afforded
the pure product in high yields.
N-(p-Methylbenzyl)benzamide (1): mp. 137–138◦C (lit.20 137◦C); TLC Rf 0.64 (50%
ethyl acetate in hexane); IR (KBr): 3305, 3025, 2918, 1633, 1540, 1488, 1441, 1315, 1295,
1228 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 8.4 Hz,

Preparation of Carboxamides and Peptieds using N-Succinimidyl Esters
373
1H), 7.34 (t, J = 8.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.87 (br,
1H), 4.51 (d, J = 5.6 Hz, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.3, 137.0,
135.2, 134.3, 131.3, 129.2, 128.3, 127.7, 126.9, 43.7, 21.0.
N-Cyclohexyl-4-methoxybenzamide (2): mp. 158–160◦C (lit.21 158–160◦C); TLC
Rf 0.33 (50% ethyl acetate in hexane); IR (KBr): 3304, 3040, 2927, 1618, 1599, 1544,
1498, 1443, 1331, 1245, 1171 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.8 Hz,
2H), 6.86 (d, J = 9.2 Hz, 2H), 6.34 (br, 1H), 4.00–3.88 (m, 1H), 3.81 (s, 3H), 2.03–1.94
(m, 2H), 1.77–1.68 (m, 2H), 1.67–1.58 (m, 1H), 1.44–1.10 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 166.0, 161.8, 128.5, 127.2, 113.4, 55.2, 48.5, 33.0, 25.4, 24.8.
N-Cyclohexyl-4-nitrobenzamide (3): mp. 161–163◦C (lit.22 160–161◦C); Rf 0.78
(50% ethyl acetate in hexane); IR (KBr): 3317, 3073, 2937, 1637, 1599, 1542, 1498,
1447, 1340, 1279 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.8 Hz, 2H), 7.92 (d,
J = 8.8 Hz, 2H), 6.10 (d, J = 6.8 Hz, 1H), 4.04–3.92 (m, 1H), 2.10–2.00 (m, 2H), 1.84–1.74
(m, 2H), 1.72–1.64 (m, 1H), 1.50–1.36 (m, 2H), 1.32–1.18 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 164.6, 149.4, 140.6, 128.0, 123.7, 49.2, 33.1, 25.4, 24.8.
N-(p-Methylbenzyl)cyclohexanecarboxamide (4): mp. 137–138◦C (lit.23 138◦C);
TLC Rf 0.81 (50% ethyl acetate in hexane); IR (KBr): 3294, 3020, 2925, 1637, 1535, 1439,
1321, 1252, 1218 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.13–7.01 (m, 4H), 6.29 (br, 1H),
4.31 (d, J = 5.6 Hz, 2H), 2.31 (s, 3H), 2.10 (tt, J = 3.2, 11.6 Hz, 1H), 1.87–1.60 (m,
5H), 1.50–1.36 (m, 2H), 1.30–1.10 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 175.9, 136.7,
135.5, 129.1, 127.4, 45.2, 42.8, 29.5, 25.5, 20.9.
N-Phenyl Dodecanamide (5): mp. 77.5–78.5◦C (lit.24 76–78◦C); Rf 0.78 (50% ethyl
acetate in hexane); IR (KBr): 3306, 2953, 2916, 2849, 1657, 1601, 1539, 1470, 1443 cm−1
;
1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.0 Hz, 2H), 7.46–7.34 (br, 1H), 7.30 (t,
J = 7.8 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 2.34 (t, J = 7.6 Hz, 2H), 1.77–1.66 (m, 2H),
1.38–1.21 (m, 16H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.6, 138.0,
128.9, 124.1, 119.8, 37.8, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 25.7, 22.7, 14.1.
Cbz-L-Ala-NH-CH2C6H5 (6): mp. 129–131◦C (lit.25 129–131◦C); TLC Rf 0.16 (50%
ethyl acetate in hexane); IR (KBr): 3290, 3029, 2987, 1712, 1657, 1638, 1533, 1433, 1252,
1
1061 cm−1; H NMR (400 MHz, CDCl3): δ 7.36–7.15 (m, 10H), 6.89 (br, 1H), 5.69
(d, J = 6.8 Hz, 1H), 5.10–4.90 (m, 2H), 4.42–4.20 (m, 3H), 1.35 (d, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 172.3, 156.0, 137.9, 136.0, 128.6, 128.4, 128.1, 127.9, 127.5,
127.4, 66.0, 50.5, 43.3, 18.7.
Cbz-L-Phe-NH-CH2C6H5 (7): mp. 139–140◦C (lit.26 140–144◦C); TLC Rf 0.28 (50%
ethyl acetate in hexane); IR (KBr): 3300, 3028, 2936, 1692, 1665, 1533, 1451, 1252,
1
1031 cm−1; H NMR (400 MHz, CDCl3): δ 7.34–6.94 (m, 15H), 6.83 (br, 1H), 5.89
(d, J = 6.8 Hz, 1H), 4.84 (d, J = 4.8 Hz, 2H), 4.60–4.47 (m, 1H), 4.40–4.06 (m, 2H), 2.99
(d, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 170.9, 155.9, 137.5, 136.4, 136.0,
129.3, 128.4, 128.3, 128.0, 127.7, 127.5, 127.2, 126.7, 66.7, 56.2, 43.2, 38.9.
Cbz-L-Phe-L-Ala-OEt (8): mp. 122–123◦C (lit.27 121.5◦C); TLC Rf 0.75 (50% ethyl
acetate in hexane); [α]2D2 = – 0.1 (c = 1.000, chloroform); lit.27 [α]1D8 = – 19.68 (c = 2.0,
ethanol); IR (KBr): 3289, 3065, 2986, 1749, 1693, 1659, 1545, 1454, 1263 cm−1; 1H NMR
(400 MHz, CDCl3): δ 7.38–7.15 (m, 10H), 6.39 (br, 1H), 6.24 (br, 1H), 5.46–5.32 (m, 2H),
5.08 (s, 1H), 4.51–4.41 (m, 2H), 4.16 (m, 2H), 3.16–3.01 (m, 2H), 1.35–1.19 (m, 6H); 13C

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Han and Kim
NMR (100 MHz, CDCl3): δ 172.4, 170.2, 155.9, 136.3, 129.3, 128.7, 128.5, 128.2, 128.0,
127.1, 67.1, 61.6, 56.0, 48.2, 48.0, 38.5, 31.6.
Cbz-L-Ile-L-Ala-OEt (9): mp. 161–162◦C (lit.28 163.0–163.8◦C); TLC Rf 0.73 (50%
ethyl acetate in hexane); [α]D22 = – 3.4 (c = 1.000, chloroform); lit.28 [α]D18 = – 9.7 (c =
1.04, Chloroform); IR (KBr): 3294, 3031, 2966, 1736, 1683, 1648, 1542, 1451, 1240 cm−1
;
1H NMR (400 MHz, CDCl3): δ 7.35–7.26 (m, 5H), 6.66 (d, J = 7.2 Hz, 1H), 5.53 (d,
J = 8.8 Hz, 1H), 5.15–5.00 (m, 2H), 4.57–4.47 (m, 1H), 4.15 (q, J = 6.0 Hz, 2H), 4.06 (t,
J = 7.6 Hz, 1H), 1.87–1.76 (m, 1H), 1.56–1.45 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 1.24
(t, J = 7.6 Hz, 3H), 1.18–1.06 (m, 1H), 0.96–0.82 (m, 6H); 13C NMR (100 MHz, CDCl3):
δ 172.7, 170.9, 156.4, 136.4, 128.6, 128.2, 128.1, 67.1, 61.6, 59.6, 48.2, 37.8, 24.9, 18.3,
15.4, 14.2, 11.4.
Cbz-L-Ile-L-Leu-OMe (10): mp. 117–118◦C (lit.29 117.5–118◦C); TLC Rf 0.56 (50%
ethyl acetate in hexane); [α]D23 = – 8.2 (c = 1.000, chloroform); lit.29 [α]D25 = – 7.1
(c = 0.845, chloroform); IR (KBr): 3304, 3031, 2962, 1751, 1690, 1648, 1539, 1455,
1
1239 cm−1; H NMR (400 MHz, CDCl3): δ 7.39–7.29 (m, 5H), 6.36–6.24 (br, 1H), 5.41
(br, 1H), 5.10 (s, 2H), 4.65–4.57 (m, 1H), 4.06 (dd, J = 7.2, 7.6 Hz, 1H), 3.73 (s, 3H),
1.91–1.75 (m, 2H), 1.69–1.46 (m, 4H), 1.28–1.08 (m, 2H), 0.98–0.84 (m, 12H); 13C NMR
(100 MHz, CDCl3): δ 173.1, 171.0, 156.2, 136.2, 128.5, 128.1, 128.0, 67.0, 59.5, 52.3,
50.7, 41.4, 37.5, 24.8, 24.7, 22.7, 21.8, 15.3, 11.3.
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